Method of producing a reagent on-board an instrument

ABSTRACT

The present invention relates broadly to production of a reagent on-board an instrument. The instrument is provided with a probe for dispensing said reagent, a concentrate chamber adapted to contain a concentrate and a diluent chamber adapted to contain a diluent. The probe includes an in-line mixing chamber adapted to receive the concentrate and the diluent to provide the reagent at the required concentration for dispensing by the probe.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.14/653,956 filed on Jun. 19, 2015 which is a National Stage ofInternational Application No. PCT/AU2013/001499 filed Dec. 20, 2013,claiming priority based on U.S. Provisional Application No. 61/745,331filed Dec. 21, 2012, the contents of all of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates broadly to producing a reagent on-board aninstrument such as a laboratory instrument for treating a biologicaltissue sample with the reagent. The invention also relates generally toan instrument utilising a reagent produced on-board the instrument froma mixture of a concentrate and a diluent.

BACKGROUND TO THE INVENTION

Immunohistochemical staining and in situ nucleic acid analysis are toolsused in histological diagnosis and the study of tissue morphology.Immunohistochemical staining relies on the specific binding affinity ofantibodies with epitopes in tissue samples, and the increasingavailability of antibodies which bind specifically with unique epitopespresent only in certain types of diseased cellular tissue.Immunohistochemical staining involves a series of treatment stepsconducted on a tissue sample (typically a section) mounted on a glassslide to highlight, by selective staining, certain morphologicalindicators of disease states.

Typical treatment steps include pretreatment of the tissue sample toreduce non-specific binding, antibody treatment and incubation, enzymelabelled secondary antibody treatment and incubation, substrate reactionwith the enzyme to produce a fluorophore or chromophore highlightingareas of the tissue sample having epitopes binding with the antibody,counterstaining, and the like. Between each treatment step, the tissuesample must be rinsed to remove unreacted residual reagent from theprior step. Most treatment steps involve a period of incubationtypically conducted at ambient temperature of around 25° C. up to around40° C., while cell conditioning steps are typically conducted atsomewhat higher temperatures, e.g. 90° C. to 100° C. In-situ DNAanalysis relies upon the specific binding affinity of probes (DNAbinding proteins) with unique nucleotide sequences in cell or tissuesamples and similarly involves a series of process steps, with a varietyof reagents and process temperature requirements. Some specificreactions involve temperatures up to 120° C. to 130° C.

In these various treatment steps it is understood that no singleconcentration of antibody is sufficient to account for tissuevariations, processing variability and tissue sample thickness. Reagentsare provided in a Ready to Use (RTU) format that cannot be varied inconcentration. Alternatively, concentrates are supplied and diluted toachieve a range of staining options. However, these approaches do notaddress increasing customer need for workflow flexibility with ease ofreagent uses.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided aninstrument utilizing a reagent, said instrument providing on-boardmixing of the reagent and including:

-   -   a probe for dispensing said reagent;    -   a concentrate chamber adapted to contain a concentrate; and    -   a diluent chamber adapted to contain a diluent;    -   wherein the probe includes an in-line mixing chamber adapted to        receive the concentrate and the diluent to provide the reagent        at the required concentration for dispensing by the probe.

The instrument may include one or more mixing wells located on theinstrument and configured to receive the concentrate and the diluent formixing to provide the reagent at the required concentration. In oneembodiment the mixing well is formed in a sample staining module (SSM)of the instrument. The mixing well may be formed in a fixed ordisposable cover member of the SSM. Alternately the mixing well may be adedicated mixing well formed integral with the instrument.

Preferably the mixing wells are located adjacent one another for serialdilution of the concentrate with the diluent.

The chamber may be a container supplied in a sealed condition andadapted to contain a predetermined volume of the concentrate. The sealedcontainer may include a sealing membrane arranged to contain theconcentrate and an inert gas. The sealing membrane may be designed to beat least partly removed or pierced and the container is sized foraddition of diluent for mixing on-board the instrument to provide thereagent at the required concentration. Alternatively or additionally thechamber comprises a plurality of the sealed containers each adapted tocontain a predetermined volume of the concentrate. In this embodimentthe plurality of chambers are arranged as multiple reservoirs e.g. in ablister pack. In another embodiment the chamber is a disposable orreusable probe tip containing the concentrate and adapted to fit to adispensing probe of the instrument.

therein some embodiments, the instrument includes a concentratedispenser for on-board provision of a reagent, said dispenser comprisingpackaging adapted to contain a plurality of concentrate capsules, thepackaging configured to release each of the capsules for mixing with adiluent on-board the instrument to provide the reagent at the requiredconcentration.

Preferably the packaging includes a stacked cartridge adapted to containone or more columns of the plurality of concentrate capsules. In someembodiments two or more columns of the concentrate capsules are providedin the cartridge. More preferably the dispenser also comprises areciprocating release operatively coupled to the stacked cartridge torelease a lowermost of the column of capsules form the cartridge formixing with the diluent on-board the instrument. Alternatively thepackaging includes a cartridge reel adapted to contain a roll of theconcentrate capsules retained in a concentrate tape configured to bedispensed from the cartridge reel. In this embodiment the concentratetape includes two strips adhered to one another with the concentratecapsules sandwiched therebetween and adapted to be released from theconcentrate tape.

Also described herein is an instrument utilising a reagent, saidinstrument including:

-   -   a diluent chamber adapted to contain a diluent;    -   a concentrate dispenser operatively coupled to the diluent        chamber to dispense concentrate for mixing with the diluent        on-board the instrument to produce the reagent at a required        concentration. the concentrate may be contained in dissolvable        capsules designed to dissolve during mixing with the diluent to        produce the reagent. In this embodiment the diluent is acidic or        basic depending on the concentrate, and the dissolvable capsules        are formed at least in part of a material which dissolves in the        acidic or basic diluent.

The diluent chamber may be a vacuum chamber to which the concentratedispenser is operatively coupled wherein the concentrate is dispensedinto the vacuum chamber with the assistance of vacuum pressure appliedto the diluent chamber. Alternatively the concentrate dispenser mayinclude a plunger for dispensing of the concentrate into the diluentchamber, preferably via a non-return valve. Still alternatively theconcentrate dispenser may include a frangible separator which cooperateswith the diluent chamber wherein rupturing of the frangible separatoreffects dispensing of the concentrate to the diluent chamber.

Generally the instrument is a laboratory instrument and the reagent is ahigh value reagent such as a molecular probe such as a nucleic acidprobe or an antibody (Ab) although that need not be the case and thereagent may be a bulk reagent such as a wash fluid or buffer which isformulated on-board the instrument from concentrate and diluent. Theconcentrate may be in any state such as a liquid, solid, or lyophilisedstate.

Also described herein is a method of producing a reagent on-board aninstrument, said method including the steps of:

-   -   providing a concentrate at the instrument;    -   discharging the concentrate into a diluent provided at the        instrument, or vice versa;    -   mixing the concentrate with the diluent on-board the instrument        to provide the reagent at a required concentration.

In one embodiment the method may also comprise one or more subsequentsteps of diluting the reagent with additional diluent to produce therequired concentration.

Also described is packaging for use with an instrument in the on-boardprovision of a reagent, the packaging being adapted to contain aplurality of concentrate capsules, and configured to release each of thecapsules for mixing with a diluent on-board the instrument to providethe reagent.

Also described is a container for use with an instrument in the on-boardprovision of a reagent, the container adapted to contain a predeterminedvolume of a concentrate for mixing with a diluent on-board theinstrument to provide the reagent.

Also described is a cover member for use with an instrument in theon-board provision of a reagent, the cover member including a well beingadapted to receive a concentrate for mixing with a diluent on-board theinstrument to provide the reagent.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to achieve a better understanding of the nature of the presentinvention a preferred embodiment of an instrument utilizing a reagentwill now be described, by way of example only, with reference to theaccompanying drawings in which:

FIG. 1A is a schematic illustration of a cover member associated with asample staining module (SSM) of an instrument having on-board productionof the reagent according to an embodiment of one aspect of theinvention; FIG. 1B and FIG. 1C show a concentrate packaged in a sealedcontainer for dispensing into the cover member of FIG. 1A; FIG. 1A, FIG.1B, and FIG. 1C may be collectively considered as a FIG. 1.

FIG. 2A and FIG. 2B are schematics of alternative embodiments of mixingwells or chambers designed for on-board production of reagents; FIG. 2Aand FIG. 2B may be collectively considered as a FIG. 2.

FIG. 3A and FIG. 3B are schematics of alternative embodiments ofchambers designed to be used in conjunction with the instrumentdescribed with respect to FIG. 1A; FIG. 3A and FIG. 3B show side and topviews respectively; FIG. 3A and FIG. 3B may be collectively consideredas a FIG. 3.

FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D are schematics of differentconcentrate dispensers designed for the on-board provision of a reagentat an instrument according to embodiments of another aspect of theinvention; FIG. 4A. FIG. 4B, FIG. 4C, and FIG. 4D may be collectivelyconsidered as a FIG. 4.

FIG. 5A, FIG. 5B, and FIG. 5C are schematics of packagedconcentrates/diluents used to produce reagents on-board an instrumentaccording to embodiments of a further aspect of the invention; FIG. 5Ashows the sealing membrane in-tact (left) and ruptured (right); FIG. 5a, FIG. 5B, and FIG. 5C may be collectively considered as a FIG. 5.

FIG. 6 is a schematic illustration of an instrument utilising a reagentand providing on-board mixing of the reagent according to embodiments ofthe invention.

FIG. 7 is a flow diagram showing steps in a method of producing reagentonboard an instrument according to embodiments of the invention.

DETAILED DESCRIPTION

FIG. 1A is a schematic illustration of a cover member 14 of a slidestaining module (SSM) 74 of an instrument 70 (FIG. 6). In oneembodiment, well 10 may be utilised as a mixing well for mixing aconcentrate 12 with a diluent (not shown) on-board the instrument 70 toprovide a reagent at a required concentration. The well 10 is in thisembodiment formed in a cover member 14 associated with a sample stainingmodule (SSM) 74 of the instrument 70 and may receive or mix reagent. Thecover member 14 may be releasably attachable to the SSM 74 of theinstrument 70. The mixing well in alternative embodiments may be formedas an integral part of the instrument. For example, in some embodiments,instrument 70 is provided with multiple mixing wells for serial dilutionof the concentrate as illustrated in FIG. 2A. In other embodiments, themixing well is a mixing chamber which is integral with a reagentdispensing probe 30 of the instrument, as illustrated in FIG. 2B.

The instrument 70 of this aspect of the invention is a laboratoryinstrument for treating a biological tissue sample within the SSM withthe reagent, typically a high value reagent in the form of a molecularprobe such as a nucleic acid probe or an antibody (Ab). The high valuereagent is produced at a desired concentration on-board the instrument70 by mixing the concentrate such as 12 and diluent to provide thereagent at the required concentration. It is to be understood, however,that the reagent need not be “high value” and may be any concentratethat is amenable to dilution to a required concentration such as, forexample, wash fluid or buffer solution which may be diluted with forexample, deionised water, to a predetermined concentration suitable fore.g. treatment of the sample or washing or other use within a covermember of the SSM.

FIG. 6 is a schematic illustration of an instrument 70 according to someembodiments of the invention, including a plurality of side stainingmodules 74 arranged to receive slides 73. At least one slide transportrobot 78 in the form of a gantry robot configured by a controller (notshown) moves the slides 73 using a slide transport device 75 (such as asuction cup) to and from the slide staining modules 74. The fluidtransport system 72 includes a fluid dispensing robot 76 configured bythe controller to dispense a plurality of reagents from a probe 30 ofthe fluid dispensing robot to the slides 73 received in the slidetreatment modules 74 to treat the tissue samples on the slides.

In some cases, to treat the tissue samples on the slides 73, adesignated combination of reagents, e.g. higher and lesser valuereagents, are required to be dispensed to a slide and in someembodiments it is desirable to achieve mixing to a predeterminedconcentration on-board the instrument. The fluid dispensing robot 76 isconfigured by the controller to dispense a plurality of reagents storedin reagent containers 80, 81 on board the instrument to the slides 73 inthe slide staining modules 74.

In the embodiment of FIG. 1B and FIG. 1C the concentrate 12 is providedin a sealed container 13. The sealed container 13 includes a sealingmembrane 18 arranged to contain the concentrate 12 within a plurality ofsealed chambers 16. The sealed container 13 of this example is in theform of a blister pack 20. The blister pack 20 is designed to releaseeach of the concentrate volumes such as 12 into a chamber such as aconcentrate chamber or a mixing chamber for on-board mixing of thereagent. In the context of FIG. 1A, each of the concentrate volumes suchas 12 is released into the well 10 of the cover member 14. The sealingmembrane 18 which is in the form of a frangible foil is ruptured orotherwise broken or removed by the instrument across an entry to thewell 10 (or instrument chamber) for release of the concentrate 12. Inthis and other embodiments, the diluent may be pumped from a bulk supplyinto the well 10 either before or after addition of the concentrate toachieve the required concentration. The reagent is thus mixed andproduced on-board the instrument for dispensing e.g. by a probe to covermember 14. The reagent may then be drawn under the cover member 14 oraspirated using a robot and a fluid transport probe (not shown) and thendispensed through a port 9 into a reaction area 11 for treatment, suchas staining.

FIG. 2A and FIG. 2B illustrate alternative embodiments suitable forproduction of a reagent on-board an instrument such as that includingthe cover member 14 of the previous embodiment of FIG. 1A. For ease ofreference and to avoid repetition, the same reference numerals have beenused for similar components of this and any other embodiments. In theembodiment of FIG. 2A the instrument 70 is provided with multiple mixingwells 10A to 10D for serial dilution of the concentrate 12. The reagent12 is at stage 1 transferred to the mixing well 10B and at stage 2diluted with diluent. The resulting reagent is mixed in the mixing well10B and at stage 3 transferred to mixing well 10C for further dilutionat stage 4 with diluent. The resulting reagent is mixed in mixing well10C and at stage 5 transferred to mixing well 10D for further dilutionwith diluent at stage 6. The final reagent at its required concentrationis at stage 7 transferred from the mixing well 10D for use by theinstrument 70. It will be appreciated by those skilled in the art thatthe number of mixing wells required for each desired dilution may varyaccording to the required dilution. Accordingly, the number of mixingwells provided or utilized may vary according to the required dilution.The final reagent may for example be used in staining a tissue samplelocated on a slide (not shown) of the SSM 74. The multiple mixing wells10A to 10D may be formed as an integral part of the instrument 70 in forexample the SSM 74 or as shown in FIG. 1A fabricated in a fixed ordisposable cover member of the SSM.

In the embodiment of FIG. 2B the instrument 70 includes a probe 30having an in-line mixing chamber 32 to provide on-board production of areagent. The probe 30 is for example in the form of a fluid transferprobe (FTP) of an instrument used for dispensing fluids for treating orstaining tissue samples on slides in the SSM 74. The modified FTP 30includes a bifurcation to a diluent chamber 34 and a concentrate chamber36 located up stream of the mixing chamber 32. The diluent andconcentrate chambers 34/36 provide the requisite volume of diluent 38and concentrate 40 to the mixing chamber 32 to provide a reagent at therequired concentration. The FTP 30 includes a nozzle 42 downstream ofthe mixing chamber 32 which is configured to dispense the mixed reagentinto a cover member 14 of a SSM 74. The nozzle 42 may discharge reagentdirectly on to the sample slide or into a port or well of a cover member14 (see FIG. 1A) associated with the SSM. In one embodiment theinstrument may incorporate a separate valve or valves (not shown)arranged on or adjacent to the mixing chamber 32. It is to be understoodthat the mixing chamber 32 may be in fluid communication with furtherconcentrate and diluent reservoirs (80, 81) and optionally, furtherconcentrate and diluent chambers (36, 34) upstream of the mixing chamber32 such that the probe receives more than two constituents for mixing,enabling flexibility in the combinations and concentrations of reagentsthat are prepared on-board the instrument 70 as may be determined by acontroller of the instrument. The concentrate reservoirs 80 may be e.g.in the form of sealed containers as disclosed herein.

FIG. 7 is a flow chart illustrating steps in a method of producing areagent on-board the instrument. The method includes, in a step 701,pumping a requisite volume of concentrate into the concentrate chamberand, in a step 702, pumping a requisite volume of diluent into thediluent chamber to achieve a required concentrate of reagent. In steps703 and 704, the concentrate is released from the concentrate chamberand the diluent chamber respectively into the mixing chamber in theprobe. In a step 705, the reagent is mixed at the requiredconcentration, and in a step 706, the mixed reagent is dispensed fromthe probe to the cover member. It is to be understood that theinstrument controller may be configured to implement the preferredmethod of on-board mixing of reagents by controlling operation of thefluid transport system 72 including the fluid dispensing robot 76 andpumping of concentrate 40 and diluent 38 from containers 80, 81respectively, into the mixing chamber 32 either directly, or throughconcentrate and diluent chambers 36, 34 located in the probe 30 upstreamof the mixing chamber as is shown in FIG. 7.

FIG. 7 also shows various instrument features 80, 20, 50 and 81, forstoring and delivering concentrate and diluent for mixing of reagent onboard the instrument.

FIG. 3A and FIG. 3B are alternate embodiments and views of a chamber orconcentrate container suitable for use with an instrument providingon-board production of a reagent. The chambers may for example besuitable for use with the cover member 14 of the instrument of FIG. 1A,or to supply the mixing wells or mixing chambers of FIG. 2A and 2B. Inthe various embodiments of FIG. 3A the concentrate such as 12 iscontained in a chamber 16 which is sealed with a sealing membrane 18.The concentrate 12 is protected from evaporation and oxidation by theuse of nitrogen or other inert gases 22 sealed within the chamber 16.The sealing membrane 18 may be in the form of a foil pack or lid seal.The embodiment of FIG. 3B is similar to the blister pack 20 of FIG. 1Bhaving multiple chambers such as 16 in a common base plate 24. Althoughnot shown the multiple chambers 16 may also be sealed with a commonsealing membrane or foil.

FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D illustrate different embodimentsof a concentrate dispenser for use on-board an instrument in productionof a reagent, for example the reagent being used in staining orotherwise treating tissue samples in an SSM of the instrument. Theembodiment of FIG. 4A schematically depicts mixing of a concentrate 12with a diluent 13 to provide the reagent as may be achieved using mixingwells and mixing chambers on-board the instrument, according to variousembodiments disclosed herein. The concentrate 12 is in this embodimentis contained in a dissolving capsule 15 designed to dissolve duringmixing with the diluent 13. The diluent 13 may be acidic or basicdepending on the chemistry of the concentrate, and the capsule 15 formedof a material which dissolves in the diluent 13. The diluent 13 may becontained in a mixing well associated with a cover member 14 of the SSMin FIG. 1A, or a mixing well, diluent chamber or mixing chamber of theinstrument as illustrated in FIG. 2A and FIG. 2B.

In the embodiments of FIG. 4B and FIG. 4C, the concentrate such as 12 iscontained in a concentrate dispenser 50 operatively coupled to aninstrument for on-board provision of a reagent. The concentratedispenser 50 includes packaging 52 within which one of a plurality ofthe concentrate capsules such as 12A to 12F are contained in a stackedcartridge. The stacked cartridge packaging 52 is designed to releaseeach of the capsules such as 12A for mixing with a diluent on-board theinstrument to provide a reagent at the required concentration. In theembodiment of FIG. 4B the concentrate dispenser 50 includes areciprocating release 54 operatively coupled to the stacked cartridge 52to release a lowermost of the column of capsules such as 12A.

In the embodiment of FIG. 4C, the packaging of the concentrate dispenser50 is in the form of a cartridge reel 52 contained within theinstrument. The cartridge reel contains a roll of the concentratecapsules such as 12A to 12F retained in a concentrate tape 56 dispensedfrom the cartridge reel 52. The concentrate tape 56 includes two strips58A and 58B adhered to one another with the concentrate capsules such as12F sandwiched therebetween. The concentrate dispenser 50 of FIG. 4Calso includes a spool 60 within the instrument for removing the lowerstrip 58B of the concentrate tape 56 to release each of the concentratecapsules such as 12A from the dispenser 50.

In the embodiment of FIG. 4D the instrument includes a chamber 16 in theform of a disposable or reusable probe tip containing the concentrate12. The probe tip 16 is designed to fit to a probe such as 44 of theconcentrate dispenser. The probe may for example be in the form of a FTPof an instrument used in treating or staining tissue samples. In thiscase the probe tip 16 includes a nozzle 46 designed to cooperate with aport of for example a cover member of a SSM. The nozzle 46 includes atemporary seal 48 which is designed to rupture on discharge of theconcentrate 12 into the well for mixing with the diluent. Theconcentrate 12 may also be sealed in the probe tip 16 with another seal49 which is similarly ruptured under the application of pressure appliedby the FTP 44.

FIG. 5A, FIG. 5B, and FIG. 5C illustrate various embodiments of adiluent chamber 17 operatively coupled to a concentrate dispenser 19 formixing on-board an instrument to produce a reagent. The diluent chamberis in the form of a mixing vial 17 with the concentrate dispenser 19attached as a single package. In the embodiment of FIG. 5A the diluentvial 17 has a vacuum pressure applied to it for dispensing of theconcentrate 12 from the concentrate dispenser 19. In the embodiment ofFIG. 5B the concentrate dispenser 19 includes a plunger 21 for urgingthe concentrate 12 from the concentrate dispenser 19 into the diluentvial 17. The concentrate dispenser 19 may include a one way valve 23through which the concentrate 12 is discharged into the diluent vial 17.The embodiment of FIG. 5C includes a concentrate dispenser in the formof the packaged chamber 16 such as the embodiments of FIG. 3A. Thechamber 16 is operatively coupled to the diluent chamber or vial 17 withits sealing membrane 18 in contact with an entrance 25 to the diluentchamber 17. The entrance 25 includes a spiked ridge 27 designed on theapplication of downward pressure to the chamber 16 to rupture thefrangible sealing membrane 18. The concentrate 12 is thus dischargedinto the diluent chamber 17 for mixing to produce the necessary reagent.

It will be readily understood by those skilled in the art that aconcentrate includes liquids of varying concentrations and for exampleincludes high-value reagents and bulk reagents. The FTP of the earlierembodiment may thus extend to dispensing a reagent to be diluted, adiluent, other reagents, or a combination of these liquids.

The instrument according to various embodiments includes a controllerconfigured to implement the preferred method of producing a reagenton-board the instrument. The method may be implemented via computerprogram code including instructions to control movement of a concentratedispenser in, for example, dispensing a concentrate to a well of a covermember associated with a SSM as in FIG. 1A, or a mixing well, diluentchamber or mixing chamber of the instrument as illustrated in FIGS. 2Aand 2B. The controller may also control dilution and mixing of theconcentrate with a diluent to provide the reagent at the requiredconcentration.

Now that several preferred embodiments of the invention have beendescribed it will be apparent to those skilled in the art that themethod of producing a reagent on-board an instrument together with theconcentrate dispenser and associated packaging has at least thefollowing advantages:

1. The concentration of the reagent produced on-board the instrument canbe varied, for example, to achieve the required staining option fortissue samples;

2. The ability to produce reagents on-board an instrument increaseworkflow flexibility with ease of use, for example by controlling theparameters of the dilution based on the supplied concentrate errors instaining are reduced;

3. On-board dilution lends itself to reagents in a liquid, solid andlyophilised form;

4. On-board dilution improves laboratory workflow without having topre-dilute reagents from concentrates and also reduces operator time andpotential errors.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. All such variations and modifications are to beconsidered within the scope of the present invention the nature of whichis to be determined from the foregoing description.

Future patent applications may be filed in the United States of Americaon the basis of or claiming priority from the present application. It isto be understood that the following claims are provided by way ofexample only, and are not intended to limit the scope of what may beclaimed in any such future application. Features may be added to oromitted from the claims at a later date so as to further define orre-define the invention or inventions.

1. An instrument utilizing a reagent, said instrument providing on-boardmixing of the reagent and including: a probe for dispensing saidreagent; a concentrate chamber adapted to contain a concentrate; and adiluent chamber adapted to contain a diluent; wherein the probe includesan in-line mixing chamber adapted to receive the concentrate and thediluent to provide the reagent at the required concentration fordispensing by the probe.
 2. The instrument as defined in claim 1,wherein the concentrate chamber is located in the probe, upstream of themixing chamber.
 3. The instrument as defined in claim 1, wherein thediluent chamber is located in the probe, upstream of the mixing chamber.4. The instrument as defined in claim 1, wherein the probe includes abifurcation upstream of the mixing chamber providing fluid communicationbetween each of the concentrate chamber and the and the diluent chamber.5. The instrument as defined in claim 1, wherein the diluent is pumpedto the diluent chamber from a bulk supply on board the instrument. 6.The instrument as defined in claim 1, wherein the concentrate chamberreceives a predetermined volume of the concentrate from a sealedcontainer stored on-board the instrument.
 7. The instrument as definedin claim 6, wherein the sealed container includes a sealing membranearranged to contain the concentrate and an inert gas, and wherein thesealing membrane is adapted to be at least partly removed or pierced bythe instrument.
 8. The instrument as defined in claim 6, comprising aplurality of the sealed containers on-board the instrument, each sealedcontainer containing a predetermined volume of the concentrate.
 9. Theinstrument as defined in claim 8, wherein the plurality of sealedcontainers are arranged as multiple reservoirs in a blister pack. 10.The instrument according to claim 1, including a concentrate dispensercomprising packaging adapted to contain a plurality of concentratecapsules on-board the instrument, and wherein the instrument isconfigured to control release each of the capsules from the concentratedispenser for mixing with a diluent in the mixing chamber of the probe.11. The instrument as defined in claim 10 wherein the packaging includesa stacked cartridge adapted to contain one or more columns of theplurality of concentrate capsules.
 12. The instrument as defined inclaim 11 wherein the concentrate dispenser also comprises areciprocating release operatively coupled to the stacked cartridge torelease, under control of the instrument, a lowermost of the column ofcapsules from the cartridge for mixing with the diluent on-board theinstrument.
 13. The instrument as defined in claim 10, wherein thepackaging includes a cartridge reel adapted to contain a roll of theconcentrate capsules retained in a concentrate tape configured to bedispensed from the cartridge reel under control of the instrument. 14.The instrument as defined in claim 13, wherein the concentrate tapeincludes two strips adhered to one another with the concentrate capsulessandwiched therebetween, and the concentrate dispenser includes a spoolfor removing one of the strips to release each of the concentratecapsules from the dispenser.
 15. The instrument as defined in claim 1,wherein the instrument is a laboratory instrument and the reagent is ahigh value reagent.